Resveratrol administration increases Transthyretin protein levels ameliorating AD features- importance of transthyretin tetrameric stability.

Luís Miguel Santos,Sara Costa Silva,Mobina Alemi,Carlos Alexandre Ribeiro,Isabel Cardoso,Daniela Rodrigues

doi:10.2119/molmed.2016.00124

Abstract

Previous in vivo work showed that resveratrol has beneficial effects in the AD pathology, resulting in increased expression of transthyretin (TTR). TTR binds Aβ peptide avoiding its aggregation and toxicity, and is reduced in the CSF and plasma, in AD. Further, resveratrol binds TTR, stabilizing the native TTR tetrameric structure. To further explore the mechanism of neuroprotection conferred by TTR in AD, resveratrol was administrated, in the diet, to 5-8 months old AD transgenic female mice carrying just one copy of the mouse TTR gene, for two months. Effects in brain Aβ burden were evaluated by immunohistochemistry, and in total brain Aβ levels by ELISA, showing a striking decrease in both parameters in treated animals. In addition, total brain LRP1 protein levels were increased in treated animals, although its gene expression was unaltered. To further understand the mechanism(s) underlying such improvement in AD features, we measured TTR plasma levels showing that TTR increased in resveratrol-treated mice, whereas liver TTR gene transcription was not altered. These results strengthen the stability hypothesis, which postulates that TTR is unstable in AD leading to accelerated clearance and lower levels. Therefore, resveratrol which stabilizes the TTR tetramer results in TTR normalized clearance, thus increasing the protein plasma levels. In turn, stabilized TTR binds more strongly to Aβ peptide, avoiding its aggregation. Our results represent a step forward to the understanding of the mechanism underlying TTR protection in AD and highlight the possibility of using TTR stabilization as a therapeutic target in AD.

Highlights

Alzheimer’s disease (AD), first described by Alois Alzheimer in 1906 [1], is the most common cause of dementia
The Aβ peptide is generated upon sequential cleavage of the amyloid precursor protein (APP), by β- and γ-secretases, and it is believed that an imbalance between
The effect of resveratrol in AD features was first assessed in terms of Aβ deposition in the AD/TTR+/– mice by immunohistochemical analysis of brain sections using the 6E10 antibody, followed by quantification using Image Pro-Plus software

Summary

Introduction

Alzheimer’s disease (AD), first described by Alois Alzheimer in 1906 [1], is the most common cause of dementia. It was shown that the major pathway for Aβ clearance is its receptor-mediated transport through the blood-brain barrier [5], which is found to be compromised in AD, with special importance in the sporadic late-onset form [6]. In such cases, an increased expression of the receptor for advanced glycation end products (RAGE), the main influx transporter of Aβ is often observed and/or a decreased expression of the efflux transporters, such as the permeability glycoprotein (P-gp) and the low-density lipoprotein receptor-related protein 1 (LRP1)(7)

Methods

Results

Conclusion